Clément K, Mosbah H, Poitou C
Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and other rare obesity with eating bevahior disorders), Nutrition Department, Pitié-Salpêtrière hospital, Paris, France; Sorbonne Université/INSERM, Nutrition and obesities; systemic approaches (NutriOmics) research Unit, Paris, France.
Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and other rare obesity with eating bevahior disorders), Nutrition Department, Pitié-Salpêtrière hospital, Paris, France.
Physiol Behav. 2020 Dec 1;227:113134. doi: 10.1016/j.physbeh.2020.113134. Epub 2020 Aug 14.
Monogenic non-syndromic obesity is characterized by severe early-onset obesity with abnormal eating behaviour and endocrine disorders. Genes contributing to these rare forms of obesity are mainly located in the leptin/melanocortin pathway, with typically an autosomal additive inheritance of obesity. The normal function of this hypothalamic pathway is essential for the control of energy balance. Genetic variants are involved in 5-30 % of severe early-onset obesity depending on explored populations. Compared to other genes in the pathway especially leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC) and prohormone convertase subtilisin/kexin type 1 (PCSK1), Melanocortin 4 receptor (MC4R)-linked obesity is characterized by obesity of variable severity with no notable endocrine phenotypes. Managing patients with monogenic non-syndromic obesity is clinically challenging since they display complex phenotypes and the obesity is often morbid and refractory to classical treatments. Until recent years, there has been a lack of effective and targeted pharmaceutical molecules except for leptin therapy that was available for leptin deficiency. The picture has changed and new promising molecules acting on the leptin-melanocortin pathway such as setmelanotide -a new MC4R agonist- are now emerging as novel targeted therapeutic opportunities.
单基因非综合征性肥胖的特征是严重的早发性肥胖，伴有异常的饮食行为和内分泌紊乱。导致这些罕见肥胖形式的基因主要位于瘦素/黑皮质素途径，肥胖通常具有常染色体加性遗传。这条下丘脑途径的正常功能对于能量平衡的控制至关重要。根据所研究的人群，基因变异在5%-30%的严重早发性肥胖中起作用。与该途径中的其他基因尤其是瘦素（LEP）、瘦素受体（LEPR）、阿黑皮素原（POMC）和前激素转化酶枯草杆菌蛋白酶/kexin 1型（PCSK1）相比，与黑皮质素4受体（MC4R）相关的肥胖的特点是肥胖严重程度不一，且无明显的内分泌表型。管理单基因非综合征性肥胖患者在临床上具有挑战性，因为他们表现出复杂的表型，而且肥胖往往很严重，对传统治疗难治。直到近年来，除了可用于瘦素缺乏症的瘦素治疗外，一直缺乏有效且有针对性的药物分子。现在情况有所改变，作用于瘦素-黑皮质素途径的新的有前景的分子，如新型MC4R激动剂setmelanotide，正作为新的靶向治疗机会出现。
